Debra L. Beck and Eugene Braunwald, MD
Semaglutide is a is a glucagon-like peptide-1 (GLP-1) receptor agonist that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease. In the global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program, Wilding et al evaluated the efficacy and safety of semaglutide at a dose of 2.4 mg once weekly in persons with overweight or obesity.
Eligible participants included 1,961 nondiabetic adults with either a body-mass index (BMI) of ≥30 or ≥27 in persons with 1 or more weight-related coexisting conditions. Participants were randomly assigned in a 2:1 ratio to 68 weeks of treatment with once-weekly subcutaneous semaglutide 2.4 mg or matching placebo, plus lifestyle intervention, which included monthly counseling to help with adherence to a reduced-calorie diet and increased physical activity. The study was conducted at 129 sites in 16 countries in Asia, Europe, North America, and South America.
There were two primary endpoints: the percentage change in body weight and weight reduction of at least 5%. Both were met.
The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group (vs. -2.4% with placebo), for an estimated treatment difference of -12.4 percentage points (p<0.001). A 5% or more weight reduction was achieved by 86.4% of the study arm and by 31.5% of the placebo arm (p<0.001). A 10% or more reduction was seen in 69.1% and 12.0%, respectively, and a 15% of more reduction in 50.5% and 4.9%, respectively (p<0.001 for both comparisons).
Body weight was reduced from baseline to week 68 by 15.3 kg with semaglutide as compared with a reduction of 2.6 kg in the placebo group (estimated treatment difference, 12.7 kg).
Participants who received semaglutide had a greater improvement in their cardiometabolic risk factors, including waist circumference, BMI and blood pressure, and a greater increase in participant-reported physical functioning.
Overall, no difference was seen in percentages of participants reporting adverse events (89.7% vs. 86.4%). Nausea and diarrhea were the most common adverse events with semaglutide, but they were mostly mild-to-moderate in severity and transient. More participants in the semaglutide group than in the placebo group discontinued treatment due to gastrointestinal events (4.5% vs. 0.8%).
Summary
The researchers concluded that in adults with obesity (or overweight and one or more weight-related coexisting conditions), once weekly semaglutide at a dose of 2.4 mg plus lifestyle intervention was associated with sustained and clinically relevant reductions in body weight. As compared to liraglutide, the only GLP-1 receptor agonist approved for weight loss, the weight loss phase with semaglutide persisted longer and reached its nadir later.
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Thanks to Debra L. Beck and Eugene Braunwald, MD for sharing their opinions on safe and effective weight loss methods.